Anti-fungal compounds

Details Anti-fungal compounds Anti-fungal compounds

1992-10-27

1994-04-19

Waddell, Frederick E.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

514858, A61K 3156

Patent

active

053045513

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to the anti-fungal use of certain steroids.
2. Description of the Prior Art
UK Patent 2161380 B (National Research Development Corporation) describes the anti-fungal, especially anti-candida use of, bile acids and derivatives thereof, collectively having the formula ##STR2## wherein each of X, Y and Z independently represents a hydrogen atom or a hydroxyl group or a derivative thereof which is a conjugate formed between the carboxyl group and the NH.sub.2 group of an amino acid, and their pharmaceutically acceptable salts.
It has been a problem to find alternative anti-fungal compounds having improved therapeutic action against various fungi invasive to the human body.


SUMMARY OF THE INVENTION

It has now been found that compounds of the general formula (7): ##STR3## wherein X is a hydrogen atom or a hydroxyl group, Y is a hydrogen atom or a hydroxyl group and at least one of X and Y is a hydroxyl group and Z is a hydroxyl group or a methylol (--CH.sub.2 OH) group, have useful anti-fungal activity. Against some fungi, at least, activity appears to be better than is obtainable from the bile salts of the prior patent. Such fungi include Candida species and the fungi implicated in athlete's foot and ringworm (Trichophyton mentagrophytes and Microsporum audonil). The compounds of the invention are of particular interest for topical application.
The compounds of general formula (7) wherein Z is a hydroxyl group are known compounds. Insofar as such compounds might have no previously described medical use, this invention comprises the first medical use thereof and insofar as they might have a previously described medical use, this invention comprises the specific second medical use thereof as anti-fungal agents, said uses to be claimed in the conventional manner appropriate to national patent law. Thus, in particular, the invention, in EPC countries, includes the use of a compound of formula (7) for the manufacture of a medicament for the therapeutic application of treating fungal infections, especially by topical application, while for US purposes it includes a method of treatment of a fungal infection in a human patent, which comprises administering to the patient, preferably topically, a therapeutically effective amount of a compound of formula (7).
The invention includes particularly a pharmaceutical composition, especially for topical application, comprising a compound of formula (7) in association with a pharmaceutically acceptable carrier or diluent.
Compounds of formula (7) wherein Z is a methylol group are believed to be novel compounds and are therefore claimed as such. These compounds have one additional carbon atom in their side-chain compared to the bile acids or the bile alcohols (Z.dbd.OH).


DESCRIPTION OF THE PREFERRED EMBODIMENTS

Investigations into the effectiveness of various bile acid derivatives has shown that the compounds of the invention have a greater activity against at least one of the three selected fungal strains than the corresponding bile salts of formula (1). These tests are reported below. They indicate in particular that the following compounds of formula (7) are particularly effective against the following organisms:


______________________________________ X = OH, Y = H vs Microsporum audonii and ("chenodeoxycholic"), Trichophyton mentagrophytes Z = OH X = H, Y = OH vs. Microsporum audonii and ("deoxycholic"), Trichophyton mentagrophytes Z = OH or --CH.sub.2 OH X = OH, Y = OH ("cholic") vs. Trichophyton mentagrophytes Z = --CH.sub.2 OH ______________________________________
The above-recited compounds or groups of compounds are accordingly preferred.
The compounds of the invention exhibit optical isomerism through an asymmetric carbon atom at the 21-position. The invention includes the individual isomers, which can be resolved by conventional means, as well as mixtures thereof.
The compounds of the invention are particularly useful in treating candidiasis and infections by derma

REFERENCES:
patent: 4681876 (1987-07-01), Marples et al.
Chemical Abstracts 107: 198742n, 1987.
Chemical Abstracts 107: 198739s, 1987.
Chemical Abstracts 107: 7433e, 1987.
Stoll et al., "Some Physical Factors Affecting the Enhanced Blepharoptotic Activity . . . ", Journal of Pharmaceutical Sciences, 1969, 58(12), pp. 1457-1459.
Goodman Gilman et al. (Editors), The Pharmacological Basis of Therapeutics (6th Ed.), MacMillan Publishing Company, New York, 1980, p. 1238 especially.
X. Zhu et al., "Allomerization of cholic acid and conversion to petromyzonol", Can. J. Chem. 65, 2447-2449 (1987).
A. A. Malik et al., "Selective reduction of the fomylated bile acids to the corresponding formylated bile alcohols analogs", Organic Preparations and Procedures Int. 19, 1-7 (1987).
A. A. Malik et al., "Selective protection of the side chain hydroxy group in bile alcohol derivatives", Organic Preparations and Procedures Int. 18, 345-352 (1986).
"Selective Toxicity" by Adrian Albert, 7th Edition, Chapman & Hall 1985, 603-606.
Marshall et al "Aspects of the effect of bile . . . " Journal of Medical and Veterinary Mycology, vol. 25, No. 5, 1987, pp. 307-318.
Bellini et al "Derivati dell'acido litocolico . . . " Farmaco, Ed. Sci. vol. 39, No. 4, Apr. 1984, pp. 305-315.

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